title: Combination treatment of angiotensin II type I receptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats.
abstract: Angiotensin II type I receptor blocker and iron chelator reportedly exert suppressive effects on nonalcoholic steatohepatitis (NASH) progression, including liver fibrosis and hepatocarcinogenesis. The aim of this study was to elucidate the combined effect of losartan (LOS), an angiotensin II type I receptor blocker, and deferasirox (DSX), a newly developed oral iron chelator, on the progression of NASH in rats. To induce NASH, F344 rats were fed a choline-deficient l-amino acid-defined diet for 12 wk, and the effects of LOS and DSX at clinically comparable low doses were elucidated in conjunction with oxidative stress, neovascularization, and hepatic stellate cells (HSC) activation, all known to play important roles in the progression of NASH. Treatment with both LOS and DSX suppressed choline-deficient L-amino acid-defined diet-induced liver fibrosis development and hepatocarcinogenesis. This combination treatment exerted a stronger inhibitory effect compared with treatment with a single agent. These inhibitory effects occurred almost concurrently with the suppression of oxidative stress, neovascularization, and HSC activation. Our in vitro study demonstrated that LOS and DSX inhibited angiotensin II-induced proliferation, transforming growth factor-β(1) expression of activated HSC, and in vitro angiogenesis. These results indicated that dual inhibition by combined treatment of LOS and DSX attenuated the progression of NASH. Since both agents are widely used in clinical practice, this combination therapy may represent a potential new strategy against NASH in the near future.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kaji
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Shirai
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aihara
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshii
authors.forename: Koji
authors.initials: K
authors.lastname: Yanase
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Tsujimoto
authors.forename: Hideto
authors.initials: H
authors.lastname: Kawaratani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001565:Benzoates / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002796:Choline Deficiency / Q000150:complications; D000077588:Deferasirox; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005234:Fatty Liver / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D007502:Iron Chelating Agents / Q000008:administration & dosage*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D020533:Angiogenesis Inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001565:Benzoates; D007502:Iron Chelating Agents; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D014230:Triazoles; D000804:Angiotensin II; D019808:Losartan; D000077588:Deferasirox